WO2000078354A1

WO2000078354A1 - Topical composition comprising acetyl salicylic acid

Info

Publication number: WO2000078354A1
Application number: PCT/GB2000/002412
Authority: WO
Inventors: Jo Klaveness
Original assignee: NORWAY MEDICAL GROUP INT AS
Current assignee: NORWAY MEDICAL GROUP INT AS
Priority date: 1999-06-22
Filing date: 2000-06-22
Publication date: 2000-12-28
Anticipated expiration: 2001-12-22
Also published as: GB9914582D0; AU5550200A

Abstract

A topical pharmaceutical composition comprising acetyl salicylic acid or a physiologically tolerable prodrug or salt form thereof dissolved in an essentially water-free physiologically tolerable organic solvent having a molecular weight of 120 Daltons or less, said composition further comprising a particulate water-adsorber, optionally being disposed in a two compartment container having a closable liquid outlet and having a porous wall between the compartments thereof, said water-adsorber being disposed in one of said compartments.

Description

TOPICAL COMPOSITION COMPRISING ACETYL SALICYCLIC ACID

This invention relates to topical liquid acetyl salicylic acid compositions and to containers containing such compositions.

Acetyl salicylic acid (ASA) , otherwise known as aspirin (formerly a trade mark of Bayer AG) , is perhaps the world's most widely used pharmaceutical. It has a wide range of uses, e.g. as an analgesic, antipyretic, antirheumatic and as a cardioprotectant . Most ASA is administered orally in tablet form; however it is also effective when administered topically in solution, e.g. in treatment of insect bites, muscle pain, etc.

ASA however is prone to hydrolysis, producing as the breakdown products acetic acid and the irritant salicylic acid (SA) and indeed in aqueous media ASA will hydrolyse almost completely in less than one week. Although various liquid ASA compositions have been proposed, e.g. solutions in lower alkanols, such liquid ASA compositions still suffer from loss of ASA activity on storage, especially following opening of multidose containers. As a result, despite its efficacy for topical treatment, liquid ASA compositions have not proved to be particularly commercially successful.

We have now found that storage stability of ASA solutions, especially stability following the opening of multidose containers, may be improved by including a water-adsorber in the composition, in particular a zeolite .

Viewed from one aspect the invention provides a topical pharmaceutical composition comprising acetyl salicylic acid or a physiologically tolerable prodrug or salt form thereof (e.g. a lysine salt) dissolved in an essentially water-free physiologically tolerable organic solvent having a molecular weight of 120 Daltons or less, said composition further comprising a particulate water-adsorber.

In an alternative aspect of the invention, the ASA or salt thereof may be dissolved in a solvent mixture comprising at least two miscible organic solvents of molecular weight 120 Daltons or less, at least one of which is volatile and water-immiscible and at least one of which is water-miscible, the composition again preferably containing a particulate water- adsorber . Viewed from this aspect the invention provides a topical pharmaceutical composition comprising acetyl salicylic acid or a physiologically tolerable prodrug or salt form thereof (e.g. a lysine salt) dissolved in an essentially water-free, physiologically tolerable organic solvent system, said solvent system comprising at least two miscible organic solvents of molecular weight 120 Daltons or less, at least one of which is volatile and water-immiscible and at least one of which is water- miscible, said composition preferably containing a particulate water-adsorber.

The ASA, if used in salt form will have as counterion a physiologically tolerable counterion, preferably an amino acid such as lysine. Other tolerable counterions include sodium and meglumine .

Suitable prodrug forms of ASA include esters which hydrolyse more rapidly in vivo than the acetyl group, e.g. compounds of formula

where R is -CH,-N

- CH₂SOCH₃ , - CH₂S0₂CH₃ , - CH₂OOCCH₃ , -

, where R_α is Ci_₃ alkyl and R₂ is C,_₃ alkyl, 2-hydroxy-ethyl or -CH₂CONH₂, e.g. -CH₂CON (CH₃) ₂, -CH₂CON (C₂H₅) ₂, -CH₂CON (iPr) ₂ , -CH₂CON(CH₃)CH₂CH₂OH and CH₂CON (CH₃) CH₂CONH₂.

The solvent or solvent system used in the compositions of the invention preferably comprises a ketone, particularly acetone, an ether, particularly diethyl ether and/or a lower alkanol, e.g. a C^g alkanol, particularly ethanol or isopropanol, especially isopropanol. Essentially water-free alkanols, i.e. containing less than 0.5% wt water, preferably less than 0.3% wt and more preferably no more than 0.2% wt water, should be used. Alternative solvents include DMSO, THF, diethyl ether, dimethyl ether, acetone, etc. As water- immiscible volatile solvents may be mentioned alkanes such as propane, butane, pentane, hexane and cyclohexane . These may of course be pressurised so as to be in liquid rather than gaseous form.

The water-adsorber is optionally a porous material which takes up water into its pores or by surface adsorption. Alternatively, it may adsorb water by reaction or by hydration of an anhydrous or partially hydrated form of a crystalline substance with stable hydrated forms. Thus it may for example be a zeolite, e.g. zeolite with a pore size of 4A or more, for example up to 10A (or where methanol is used as a solvent, a pore size of 3A) . Preferably a zeolite having a pore size of up to 6A, more preferably up to 5A, e.g. 3 to 4A, will be used. Such zeolites are available commercially, e.g. from Fluka . However calcined silica, alumina or silica-alumina or modified starches (e.g. the hydrolysed starch graft copolymers proposed for use in diapers or used in gardening as water retainers - see also GB-A-2009201 and EP-A-74179) , or anhydrous or partially hydrated salts, such as metal sulphates (e.g. magnesium sulphate or sodium sulphate) may alternatively be used. Water retainers, e.g. modified starches, developed in the 1980s by Henkel for diapers and sanitory pads (see the patent publications of Henkel) , and now used in gardening are typified by "soil -moist " , available from Sinclair, Linconshire, UK. The water- adsorbers used should preferably be substantially water free when incorporated into the compositions of the invention. Particle size is preferably 10 to 4000 μm, especially 50 to 2000 μm.

Desirably, the composition of the invention is in a two compartment container with a porous wall between a major and a minor volume compartment with the water- adsorber disposed in the minor volume compartment . Such a porous wall may be a simple barrier or it may enclose the minor volume which in that instance may for example take the form of a sachet disposed within a larger container. The porous wall may for example be a mesh or web of plastics or other material not subject to degradation by the solvent system. The pore size of the porous wall should desirably be such as to confine the water-adsorber to the minor-volume compartment .

The container for the compositions of the invention is preferably collapsible incorporating a non-return valve at the liquid outlet so as to prevent air entering the container when a dose of the composition is removed. Such a valve may be a simple flap or resilient walls to an outlet duct which keep the duct closed unless pressure is applied on the container to squeeze out a dose of the composition. Where the container walls are collapsible, the container is preferably provided with an external support, e.g. an external container or sheath, so that it may be stored and handled with ease. Thus in one embodiment the container may take the form of a flexible sac disposed within a syringe like shell having a barrel containing the sac, a nozzle connected to the sac-outlet, and a plunger disposed within the barrel for compressing the sac.

Such containers for ASA are novel and form a further aspect of the invention. Viewed from this aspect the invention provides a pharmaceutical composition comprising acetyl salicylic acid or a physiologically tolerable prodrug or salt form thereof (e.g. a lysine salt) dissolved in an essentially water- free, physiologically tolerable organic solvent having a molecular weight of 120 Daltons or less, said composition further comprising a particulate water- adsorber, said composition being disposed in a two compartment container having a closable liquid outlet and having a porous wall between the compartments thereof, said water-adsorber being disposed in one of said compartments, preferably the compartment not provided with said liquid outlet.

In the compositions of the invention, the ASA or ASA salt is preferably present at from 0.5 to 30% wt , more preferably 1 to 20% wt, especially 3 to 10% wt of the solution weight. The water-adsorber is preferably present at from 0.5 to 100% wt, more preferably 1 to 20% wt , especially 2 to 10% wt relative to the solution weight. Typically, suitable compositions of the invention are formulated from 100ml of solvent with 0.1- 40 g, preferably 0.5-20 g, especially 1-10 g of ASA and 0.1-10 g, preferably 1-5 g, especially 2-4 g of water- adsorber.

Besides solvents, ASA and water-adsorber, the compositions of the invention may contain other optional components, e.g. aromas, lubricants, stabilizers, moisturizers, fillers, pH modifiers, chelating agents (e.g. EDTA, DTPA, NTA, DOTA, etc) , gel forming agents, further active agents etc. Such additives include glycerol, aloe vera, DMSO, PEG (e.g. of 4-20 kD molecular weight) and mono- di- or tri- glycerides . Particularly preferably, the composition contains glycerol which acts as a stabilizer and a skin moisturizer. Also particularly preferably the compositions contain aloe vera, a plant extract which cools and smooths the skin. In place of aloe vera, the acetylated-mannan component of aloe vera, known as acemannan, may be used (see US-A-4735935 and US-A-4851224 ) .

Glycerol is preferably employed in amounts of 1 to 20% wt, more preferably 2 to 14% wt, especially 5 to 10% wt, relative to solution weight. Aloe vera, which is preferably used in pure gel form, is conveniently used in an amount of 0.1 to 10% wt , preferably 0.3 to 5% wt, especially 1 to 3% wt , relative to solution weight.

The compositions of the invention may be maintained in a particular pH range to further inhibit the degredation of ASA. Typically, the pH is maintained in the range pH 5-8, preferably pH 5.5-7.5. This may be achieved by the inclusion of pH modifiers, such as pH buffers, e.g. a phosphate buffer.

The liquid compositions of the invention may be applied topically by spraying, pouring or rubbing, e.g. in doses of about 0.1 to 10 mL, preferably 0.25 to 1 mL. Multiple-use containers, e.g. of volume 10 to 500 mL, especially 25 to 250 mL are accordingly preferred. It is especially preferred that the containers should be arranged to deliver a metered dose of desired volume (e.g. as a spray or a liquid aliquot) .

The compositions of the invention, especially when in gel form may be in transdermal patch form, e.g. for application by iontophoresis.

In an alternative aspect, the ASA is stabilized by binding of the carboxyl group to an ionic exchange resin, especially one in particulate form, particularly one of particle size up to 1000 μm, more particularly up to 5 μm, especially up to 500 nm. Viewed from this aspect the invention provides a pharmaceutical composition comprising a particulate ion exchange resin with bound to the surface thereof an acetyl salicylic acid, said composition optionally further containing at least one non-aqueous solvent or matrix, e.g. a gel, ointment, salve, etc. The compositions of the invention will now be described further with reference to the following non- limiting Examples and the accompanying drawings in which:

Figure 1 is a schematic cross sectional view of a first container for ASA according to the invention; and

Figure 2 is a schematic cross sectional view of a second container for ASA according to the invention.

Referring to Figure 1 there is shown a spray container 1 containing a sachet 2 containing a zeolite 3 and a solution 4 of ASA in iso-propanol and glycerol. The container is equipped with an atomizer spray head 5 and a removable sealing cap 6.

Referring to Figure 2 there is shown a flexible sac 7 disposed within syringe barrel 8 and containing ASA solution and a sachet 10 containing a zeolite 11. The syringe nozzle 12 is constricted and provided with a removable sealing cap 13. Solution from sac 7 is expelled by applying pressure to syringe plunger 1 .

EXAMPLE 1

ASA Liquid Composition

A liquid composition is produced using the following components :

Acetyl salicylic acid 6 parts by weight

Isopropanol (anhydrous) 85 parts by weight

Glycerol (anhydrous) 6 parts by weight

Zeolite UOP 4A (Fluka 3 parts by weight catalogue No. 68937) (dry)

The components are mixed, filled into containers and sealed under a dry nitrogen atmosphere.

Example 2 Storage of ASA composition with sodium sulphate

Acetyl salicylic acid (ASA) (5g) was dissolved in isopropanol (100 ml) . The solution was filled into 2 vials (10 ml in each) . Sample 1 is the reference sample while to sample 2 was added anhydrous sodium sulphate (Merck) (2.0g) . Both samples were stored for 15 minutes in an exicator with an atmosphere of air saturated with water, at room temperature (open vials) .

The vials were closed, shaken and stored for 60 days at room temperature. The samples were analysed by capilery zoneelectrophoresis (CZE) for ASA and salicylic acid (SA) .

CZE was performed on a fused silica column using 25 mM borate buffer pH 9.4, 15 kV and UV-detection (214 nm) .

Results: Ratio ASA/SA:

Sample 1 (reference ) : 12.3 Sample 2 (sodium sulphate) : 21

Example 3

Room temperature storage of ASA composition with magensium sulphate

ASA (5g) was dissolved in acetone (100 ml) and phosphate buffer (pH7, 3ml) was added. The mixture was stirred for 5 minutes. The solution was filled into 2 vials (10 ml in each) . Sample 1 is the reference sample while to sample 2 was added anhydrous magnesium sulphate (Merck, l.lg) . Both samples were stored at room temperature for 6 days and analysed by CZE as in Example 2.

Results: Ratio ASA/SA:

Sample 1 : 27 Sample 2: >53

Example 4

High temperature storage of ASA composition with magnesium sulphate

ASA was dissolved in acetone and phosphate buffer added as in Example 3.

The solution was filled into 2 vials (3 ml in each) . Sample 1 is the reference sample while to sample 2 was added anhydrous magnesium sulphate (250 mg) . Both samples were stored at 50°C for 6 days and analysed by CZE as in Example 2.

Results: Ratio ASA/SA Sample 1 8.6 Sample 2 54

Example 5

Storage of ASA composition with zeolites

ASA (5g) was dissolved in DMSO (100 ml), and water (2 ml) added.

The solution was filled into vials (1 ml each) , "water absorbers" added and the vials stored for 6 days at 50°C. Samples containing zeolite molecular sieves (Fluka 69834, 175 mg, or Aldrich 23,366-8, 140 mg) contained less SA than the reference sample (with no drying agent addition) .

Example 6

Storage of ASA composition at low pH with sodium sulphate

ASA (5g) was dissolved in acetone (100 ml) and aqueous sodium hydroxide solution (0.1 N, 10 ml) was added. The mixture was stirred for 5 minutes and filled into 2 vials (each containing 10 ml).

Sample 1 is the reference sample. Sample 2 contained anhydrous sodium sulphate (2.4g).

The samples were stored for 3 days at room temperature. Both samples were analysed for ASA and SA.

Results: Ratio ASA/SA Sample 1 27 Sample 2 39

Claims

1. A topical pharmaceutical composition comprising acetyl salicylic acid or a physiologically tolerable prodrug or salt form thereof dissolved in an essentially water-free physiologically tolerable organic solvent having a molecular weight of 120 Daltons or less, said composition further comprising a particulate water- adsorber.

2. A composition of claim 2 wherein said organic solvent is a Ci-₆ alkanol.

3. A topical pharmaceutical composition comprising acetyl salicylic acid or a physiologically tolerable prodrug or salt form thereof dissolved in an essentially water-free physiologically tolerable organic solvent, system, said solvent system comprising at least two miscible organic solvents of molecular weight 120 Daltons or less, at least one of which is volatile and water-immiscible and at least one of which is water- miscible .

4. A composition of claim 3 additionally containing a particulate water-adsorber.

5. A composition of any of claims 1 to 4 wherein said particulate water-adsorber is chosen from a crystal substance with stable hydrated forms, a water-reacting substance, a porous material which takes up water into its pores, a silica, an alumina, a silica-alumina and a modified starch.

6. A composition of any of claims 1-5 wherein said particulate water-adsorber is added in an amount in the range of 0.1-10 g per 100 ml of solvent.

7. A composition of any of claims 1-5 wherein said acetyl salicylic acid or a physiologically tolerable prodrug or salt form thereof is added in an amount in the range of 0.1-40 g per 100 ml of solvent.

8. A composition of any of claims 1 to 7 wherein said particulate water-adsorber is a zeolite.

9. A composition of any of claims 1 to 8 wherein said particulate water-adsorber is a metal salt.

10. A composition of any of claims 1 to 9 wherein said particulate water-adsorber is magnesium sulphate.

11. A composition of any of claims 1 to 10 wherein said particulate water-adsorber is sodium sulphate.

12. A composition of any of claims 1 to 11 additionally comprising at least one agent from the group of aromas, lubricants, stabilizers, moisturizers, fillers, pH modifiers, chelating agents, gel forming agents and further active agents.

13. A composition of any of claims 1 to 12 wherein the pH is maintained in the range pH 5-8.

14. A composition of any of claims 1 to 13 additionally comprising glycerol .

15. A composition of any of claims 1 to 14 additionally comprising aloe vera.

16. A pharmaceutical composition comprising acetyl salicylic acid or a physiologically tolerable prodrug or salt form thereof dissolved in an essentially water-free physiologically tolerable organic solvent having a molecular weight of 120 Daltons or less, said composition further comprising a particulate water- adsorber, said composition being disposed in a two compartment container having a closable liquid outlet and having a porous wall between the compartments thereof, said water-adsorber being disposed in one of said compartments.

17. A composition of claim 16 disposed in a container of claim 13 wherein said water-adsorber is disposed the compartment not provided with said liquid outlet.

18. A composition of claim 16 disposed in a container of claim 13 wherein said container is a collapsable container, incorporating a non-return valve and optionally disposed within an external support.

19. A composition of calim 16 disposed in a container of claim 13 wherein said compartment containing said water-adsorber is in the form of a sachet.

20. A pharmaceutical composition comprising a particulate ion exchange resin with bound to the surface thereof an acetyl salicylic acid, said composition optionally further containing at least one non-aqueous solvent or matrix.